ATS Assemblies & Sections

You're listening to the Assembly on Allergy, Immunology and Information Podcasts, brought to you by the American

Thoracic Society.

Well, hi, and welcome everyone to this episode of the ATS All podcast.

I'm Sara Assaf, I'm an assistant professor of pulmonary and critical care, the University of New

Mexico, as well as the Chair of the Web Committee of ATS All. And today's episode,

we're going to try to dive deeply into the evolving landscape of COPD management,

and to do that, I'm joined with a great line-up of experts. I would like to

first introduce Dr. Klaus Rabe, with a professor of medicine at the University of Kiel. He's a specialized

in attractive long diseases and joining us from Germany, so thank you so much. Thank you,

thanks for having me. Next I would introduce Dr. Bhatt, he's a professor of medicine

and endowed professor of airway diseases, as well as the director for the center

of flung analytics and imagery search. I'm the primary function and exercise

physiology lab at the University of Alabama. Thank you, Dr. Bhatt, for joining us. Thank you

for having me. Dr. Nick Hanania is our next speaker. He's

the director of airway clinical research center, as well as the professor of medicine at bale or college of medicine.

And the PCCM chief at Bantab Hospital in Houston. Hi, Dr. Hanania.

Hi, Dr. Hanania. Thank you for having us. Thank

you. And Dr. Stephanie Christensen. She's joining us from UCSF. She's an associate professor and the division of ordinary critical care, allergy and

the... Hi, Dr. Hanania. Thank you. Thank you all for joining

us. So without further ado, we're going to start with our first question.

We know about the COPD being, you know, heterogenous disease. And traditionally, we've known a lot

about typlone and typlone and flammatory pathways, but now we're talking more about the typlomechanism.

So like to start by breaking though, that was under time. And trying to see what is the

specific role of typlone inflammation in COPD.

So I can maybe start and then see what my colleagues say, but it's an exciting time for COPD. Because

I, and remember, 31 years ago when I started my clinical work, we thought about

it as a one size fits all. And we thought, this is a disease that is packed out by aero

obstruction. There's nothing we can do. The patients are going to die. We're going to smoke until they die. But now we have

a new look. One is the treatable disease. Second, it's actually a heterogeneous disease, like you mentioned

Sarah, but not only that, it's not only heterogeneous with the presentation of these patients and the phenotypes,

but we know that there are at least three mechanistic inflammatory pathways. A commension

type one, type three are the most common, and that news are characterized by nitrophilic inflammation.

And it's very hard to treat because they don't respond to anti-inflammatory, the one that we use at least. And then

the type two is the new kid on the block, I would say. We were used to it in the asthma field, as you

know, I wear both heads, but for many years we do not think that COP patients may have actually

type two inflammation, driven by both the innate immune system and the adaptive immune system,

the adaptive immune system may vary to allergens and other exposures, but the innate immune system may vary to pollutants and

other exposures and both drive very similar downstream signal through cytokines,

delia cytokines first, but also the type two cytokines, that I'll four, I'll five, I'll 13,

driving is an affiliate recruitment, to the airway, mucus, hyper-secretion, remodeling,

friction, and of course the symptoms and exacerbation, that is associated with

it. So that's exciting. We have a new type of COP that we can have it. Now it's 32-40% of patients,

but it's an important group of patients. I think if I may add

some thing, I think it's it's the right questions that of what has happened recently in this

in inflammatory science, if you want to run. On the other hand, to add to this

clinically, this remains a very heterogeneous disease. And I think one of the reasons

why we probably have been falling back, you had other disciplines to develop a taste and

a motivation for a personalized treatment is because of that

hydrogen. So I think the secret lies a little bit in the problem about calling the disease

as heterogeneous with one name, according to its COPD. While we all acknowledge the

all that are doctors and clinicians, that someone that has severe amphasema with the high CO2,

that is on a non-invasive ventilation, surely, is different from someone that has chronic

bronchitis, flare wraps and flammative responses with a certain cellular endotype. So for

us what's so exciting is, is that we were a little at a loss clinically about the heterogeneity.

Now translating this into inflammatory endotypes through drugs has helped I think all

of us in the program to reset our vision of where the segmentation

at the order, about this disease probably better lies, to manage the disease better. That's for me,

the something that is happening over the last years, which I found extremely rewarding for patients.

I think one of the other, you know, as you're kind of getting, you know, we're really still actually learning a lot

about these endotypes, you know, it's not necessarily the same thing as asthma. These are older

patients. They may have had a lot of deconditioning over a long period of time. They all have, you know,

by definition, have 50 facts. And so we're still learning about, okay, well, are there some patients

who have both type two and type one type three inflammation, kind of at the same time, and how do those people respond to where

therapies, how well, you know, inverses somebody who's really a much more very type

two or very type one and type three. And I think we're still actually learning about some of this heterogeneity, so

that will be even a able hopefully over time as we learn more and see more of the trial data come out, be

able to kind of understand better, who's really going to be a responder, who's really not going to be a responder, how do we treat these patients better

and hopefully as we learn more from some of the other biologic better being studied, you know,

alignment based or even some of the drugs that are kind of in

earlier trial stages, I'm hopeful that will actually see like a lot more about what that heterogeneity

really works like, so I think it's it's the very exciting time and and maybe the fact that some of the drug companies

are so interested in this now means that we're actually seeing a lot of real-time kind of human data come out, really,

understand. Yeah, I think we've talked about precision medicine for a long time and then most

of our efforts have mostly been structural phenotyping, clinical phenotyping with not really much to do to modify

the course and we've been drawing the same medicines at all the people, hoping for similar responses, obviously without

getting the same response. So I think the whole movement toward endotype, I think it's really exciting and

I think Stephanie brought up a good point that these are still not clean endotypes, I think most patients have a mix of type 1, 3

and then type 2 inflammation. So I think we should keep that in mind when we treat our patients and look for the responses

that we're expecting, which sometimes we get and sometimes we don't. Well the interesting notion is I think we

all share this enthusiasm that this feeling is moving

after a decades of storm and a lack of drug-developed, but I think what's

very interesting to me is that the main driver is the intervention. So it's all very well that we explain

the immunology now a lot better and we learn from this, but it'll be honest.

One of the accelerator has been in an intervention that is targeting a certain step

and you say, "Hey, how? Your clinical parameters prove it to a meaningful extent." And

then you think backwards, which I think is very important. So when we talk about maybe biomarkers later,

these 300 cells from miculator were in documents that were talking about the use of an L steroids.

I mean, let's face it. I mean, there was the thinking that there is something in this inflammatory response,

but coming up with something which started to personalize as Assyria was saying, gave us better clarity

and drove us into the different areas that we drove

and initiated more developments in those people that make these drugs and it's a self-accelerating sister,

which that makes so exciting. Yeah, I know when when when when I was in the medical school,

we learned about a bootloader's thing puffers, right? And now there's this more undertaking, this more phenotyping,

pretty much an exciting, you know, framework. So when we're seeing our patients and clinic,

we see a lot of COPDUs who are optimized on their inhaler therapy, but they're still having quite a bit

of symptom burden. There's still frequently exacerbating. So how can we use this and

the typing and email typing, reshape the care that we're providing for our COPD

patients. And can we talk more about precision medicine and this personalized approach that we all kind

of discuss. Sure. I think one of the things that

we shouldn't forget before we move to precision medicine also is that there are several interventions that pretty much work for most

people. When we say optimized, we want to make sure that they're truly optimized with relatively inexpensive, safe,

easy to use medications. For example, we want to make sure they're they've quit smoking. If they're smoking is

a risk factor for them and is an ongoing thing. If we want to make sure they've taken their immunizations, they do decrease

exacerbation frequency. Hopefully, they've gone to pulmonary rehab, which also decreases exacerbation frequency.

They're using their inhalers on time and are compliant with them. If they need social assistance, something we

should make sure that if we provide that and then also make sure they're using their inhalers correctly. So a lot of people make

significant critical errors in how they're using their inhalers and may not be getting the medications. Once all this is sorted out,

I think we need to then phenotype them and see if they're frequent exacerbators because there's always a risk benefit that you have to evaluate

before you start new treatments. And there I think is the commonly accepted which holds is in a two-moderate exacerbations

of one exacerbation in the previous year. But I think the field is also slowly moving towards every single exacerbation

being important and not necessarily having to wait for two or three exacerbations before escalating treatment.

I agree. One of the things we miss on this is the patient, you know, who is the really the focus

of attention. We sometimes as physicians and clinicians, we just are there to prescribe medicines,

but we don't know the receiving end. What do they impact? Actually, I was reading an

abstract at ETS last year. I don't think it's a paper yet, but there was a survey on both new patients and existing

patients. And what are the expectations of these patients? But majority of patients are actually more than a third

of these patients along all the questions. One is to get better, get active, not

have emergency room visits or hospital admission, and go back to work. So, I think

the levelling the expectation of care is part of a precision medicine approach. It's not just about

new drugs and new biological, but getting shared decision making in the equation. It's very, very important.

And I think some of that comes to the, like, you know, what is an exacerbation? What does that mean for your health,

right? Like that that exacerbations can be just as bad as things like heart attacks or

other, you know, big, or morbid problems, and lead to increased mortality increase

in some burden, re-hospitalizations, all of these things that we really want to

for patients to not be experiencing. And I think there's, you know, sometimes they

reset their levels, reset their, their expectations because they don't realize they're like, okay, well, you

know, I got some steroids and I feel better and like, what do you feel back to your baseline? It's like, no, I haven't felt back to my baseline

for years and they kind of keep having this kind of low and continued spiral and trying to understand, hey,

we should be preventing these, which means, yeah, you should be taking your inhalers daily.

We really do need to work on that. You should be trying pulmonary rehab and if we can get to and if we've kind of exhausted

those things and we can get to on a drug that be beneficial above and beyond these,

which a lot of patients need, like the triple therapy studies, you know, I think almost

50% of patients were so exacerbating, despite those are the patients that are going to do the best on these therapy,

like they're being watched, like hot, though, the fact that you're still having these vaccinations, these

symptoms, this kind of continued slow decline, really getting patients on board that, hey, we can, we

can work on this to try to like prevent you from feeling that we're sober time, like think about how you felt two years

ago, for years ago versus how you feel not, we know how can we kind of, you know, prevent that

forward progression. And so I think some of it is for me, it's like really working on that level setting

and doing that a lot of that teaching to patients and actually to other providers, because I think

a lot of um, you know, it's, I think there's a lot of providers that don't realize how

impactful. Yeah, but I guess I, I, I fully agree with this, but I made

pickup with what Nick was saying is this, this area of what it's a patient expectation. And I think

again, that brings us to the hydrogen heat of this disease, because their expectations will

be very different. I think we've been focusing very much for very good results or exacerbations,

part of this, because clinical trials and the legislation around registering drugs is around exacerbations.

But the majority of patients that we see in primary care seeing, and this is, again, heterogeneity, the care gets.

The patients that I think we all see are at an end of a spectrum that have seen other doctors.

They have a long career of the disease. They may have terminal illness, with a high-capacinate,

they have a sort of ventilator support. They are severely dysnoic and they may in a minute access. So I think

what we all saying is that we need with all the personalized therapy, you're

talking, I think in this panel with dogs and we, I think none of us forget this.

That we care for individuals with all their debris and I think we all are very careful

in understanding that novel therapy, such as biologics received,

are for a segment of this huge population worldwide. For some segments,

it works miraculously well, but there's a huge group of individuals who are simply, they are clinical characteristics

where we have to say we're not there yet and I think that is I think is a very important point to make

in terms of expectations as well and when we go to the media and we write the nice paper and we all very proud of it

and then you go on the local media and we say this is a new drug. I mean, my secretary hates me because

then you get these people calling in with all sorts of diseases but they think I've heard about this new miracle drug

and I have to say in many, many cases, no I can't because you're not falling into this categories and

heterogeneity also means you have to disappoint individuals to a certain extent of advanced diseases

and illisten. Unfortunately, you don't fall into this fortunate gap and I think that's something I think we all

need to get a cross that we manage expectations from patients but also from other colleagues and caregivers in

the right proper way and I think that's what Nick was saying just too, too, too, to Nick standard a very much move it

well said. And as Nick was mentioning, you know, he talked about

some inflammatory markers and the cascade for T2 inflammation and to Ruken 5 and

to Ruken 13 and to Ruken 4. Can we detail more the roles of those cytokines and what do we

know so far from the studies and the clinical trials about the T2 inflammatory pathway and targeted

therapies, we can also mention as well alarms and what we know

so far from the study.

So Dr. Hanania, would you mind starting more? Yeah, that's a lot of Obviously cytokines are important, but you know these type 2 cytokines are very important, but then let's not forget

there are also petitions cytokines right there that are the master planers they work in

propagating both type 2 and type 1 type 3 inflammation. But when it comes to type 2 inflammation since this is the

focus of this webinar uh, with some about IL-13, IL-5 and

IL-4. I mean, IL-5 is really very important in using the phylic recruitment.

Keeping using it was happy, not sureing them, preventing them from dying. It has other

functions. It has functions with remodeling and other things, so it's not just using the phylic.

IL-4 is a very important side to count because it does uh, does work in ISO switch

over the b-cell and IT production. So in allergic to OPD, there is such a group by the way.

We always think allergic is asthma. No, there are allergic COPD and we have a Stefan and I

involved in clinical trial and I'm looking at COPD patients with allergic sensitive. So I, for it's very important

in both using clinical recruitment but IG production. I think 13 is a, is a pre-atropic

side to kind. It's actually, it's a jack-of-all trade I call it because it's actually very important one

to block because it can increase mucus hypersecretion, it can contribute to every

modeling. It's certainly can fact-years in a phylic recruitment, but also airways with muscle

hypertrophy. And so I think all three play orchestrate together

if they type to inflammation. Each one has a specific function and certainly blocking one or the

other or both may have beneficial effect downstream. In intellected individuals,

I agree with class and everybody else that not everyone would see a PD would be candidates for

tech-to-biologic and it's estimated maybe five to eight percent of the severe COP population, many

or all the population of COPD may be candidates for the ones we have at least right now. So it's

a small portion but a very important important. And I can speak a little bit to the data that

drives who might be candidates. So the mostly, you know, we have to follow clinical trial data for best evidence-based

practice with a little bit of personalization based on who we're seeing and putting multiple pieces of information together.

But right now the approved drugs, when Dupileumab and Mepilismab are both targeting type

2 inflammation, which is more modifiable than type 1, type 3 as we, where we stand now.

So mostly they are targeted to people with frequent exacerbations. Often defined as two moderator, one severe in the previous

year and with optimal therapy, ideally triple therapy as long as they can tolerate all three components.

And then to have type 2 evidence of type 2 inflammation and some people call it Eucinophilic COPD, some people

call it COPD type 2 inflammation. So the general cut off is around 300 Eucinophils per microlata, but obviously it's

on a continuum. So in the original metrics and metryl studies, looking at a population map which

had mixed results, the inclusion criterion was Eucinophils of 150 at screening

or 300 historically. And they found that the metrics study which included both with stratified

by high and low Eucinophils. It was overall not a successful study, but in the pre-specified analysis when they looked at

half the population with high type 2 inflammation, there was an 18% reduction in exacerbation frequency.

And then in the material study, again it fell short, it was also an 18 to 20% reduction, but the paper, as you

just fell short of significance. And then more recently, they designed the Matini study where they flipped the Eucinophilal thresholds

a little bit, so they want they had to include people with 300 Eucinophils at screening and 150 historically.

And they found it 20% reduction in exacerbation frequency. And then we know of the dipillum app studies, Boreas and notice

which had almost identical results. They were used in Eucinophilal threshold of 300 %%%%%%%%%%%%%%%%%%%%.

So I think these results are quite impressive for exacerbations but they also have significant impact on other components. So in the Boreas and notice studies there was also a almost 83 ML improvement in FV1 which was quite quick within about two weeks of initiation of treatment compared to placebo and then there was also a significant improvement in quality of life and daily symptom burden. So I think these are the data points

that guide us as to which drug to use and these are the two approved therapies for type to inflammation right now.

And what biomarkers are available for us to you know a better pinpoint what would be the the best treatment

for the best patient. I know we're still having a long path in terms of biomarkers

for COPD but what do we know so far about laboratory biomarkers and acute

features or other strategies that clinicians can use. You know better align the target at therapy

with the right patient. Well I think it's mentioned but the funny thing is before

we get to the things that you measure all the factors all the type two cytokines like our

for our 395 and not the biomarkers that we use which is interesting in itself. So we use

in fact the mirror of the events that decide to kinds orchestrate.

I think that's what I would look at this. So we look a bit of the the back side mirror what is orchestration.

So basically we look at the effects of what we presume is the resultant of the cytokine being

present without knowing in what concentration what cytosine is in fact. Sounds complicated but I think for

the listeners that's an important thing to know since these cytokines have some form of overlap

and redundancy. You will have to conclude from the biomarkers that you have that

one, two or the mixture of them is orchestrators, but still that level of precision to

know exactly which one it is in our honesty. So we have if you want we have clinical

biomarkers which is a biomarker in itself to be symptomatic, have a prolonged function and they've been exacerbating.

I would call it that is called BAA, a clinical biomarker in a true sense. There we have

imaging biases, you know about the mucresplucking story, you know about sort of the averages. So imaging

provides also markers and I think they always get a little bit out of sight, but we as doctors

will use the most most importantly, that's it. And then you have the

acenophils, which miraculously seems to be working in different diseases in the cattle of 300 microlitus per mile. We

were just still in the surprise how constant that finding is indicating a risk for instability.

So the acenophilia is probably the most prominent and most reliable market that we have of our. You have

phenol, which for asthma is clear, for superde is less clear, that's evolving,

and the trials would indicate that there's also a signal there that may and will be able to contribute. And then

you have another type two marker, which is which is IGE, which is interesting, because classically

it's been related to allergic disease, sensation or debut, but there's no doubt in my mind. And since

Ben Barrow borrows data almost a hundred years ago, if you smoke you get older,

you may have increased IGE left. So there are other factors that are not classic related allergic sensation that

would increase this biomarker as well. So it's the three that we have, but I think for most sense and

purposes for the clinic trials, and I'm curious to see what my US colleagues would say. US colleagues would say,

US NFL's are a present, the Joker, the most prominent Joker that people hold

in their hands. That's the best carpeter. I think you seem to be having a present, that's at least my impression. Over to you guys.

Yeah, I think US NFL's certainly are important, but again, there are lots of issues with that. None of the biomarkers

we have right now are ideal. One is esophys can fluctuate, and certainly

can. Historic isn't, for us actually, as important, in fact, there was a paper from the

East London group, looking at his NFL over time. There's some fluctuation. So I look in

my patients in clinic, I look at, I have access to their epic, and I can do the EMI,

I can look backwards and look at his NFL. Not just one time, and you can see they fluctuate, yes, we 300

has been using clinical trial as cutoff, but actually there are some data from the clinical trial showing that

actually the response to biological may be seen even with lower ventry hundreds. The jury is still

out there, we need to decide, you know, but then there's some emerging data from the asthma

literature, and hopefully we'll see it more in COPD, that composite biomarkers may be actually a better way to look at these patients.

In asthma, we looked at these years and phenol together, and they were actually when you merge

both of them together, they are more meaningful, prognostically, but also predictive

biomarkers. I have to say that they're all of phenol and COPD still up there, you know,

we talked, you know, sorry, Stephanie and Klaus and I were investigators

on one of the large trials with Boris and notice, and we did look at, you know, a cutoff of 20 parts per billion,

why we chose 20, not 25, and asthma, which we don't know, but in general, you know, was a predictive

biomarker, if it was high, but in smokers, and you know, smoke exposure can lower, you know,

it may not be very helpful, but also, you know, has fluctuation from day to day, and so one has to be careful that

one reading may not be enough. I personally, in the clinic, I'm not measuring pheno and also your place,

but I do measure blood years and if there's maybe I'm wrong, maybe I should be, but I think

we need to look more about pheno stability and the utility. And since your PD, there's

some data to show that it is a predictive, a prognostic biomarker as well. Yeah, I think the

trial data isn't very at for pheno, but I think it's really provocative what we've seen and we don't

know if like parents smoking just means, hey, you've actually got a lower threshold and that it's still useful,

but you have to be looking at lower levels to say, you know, what's actually high in a current

smoke or is it just not useful? So I think we just don't know that answer very well yet,

but I, so I think that the data there is, it's just not, we don't have a, so I agree with you. I don't check, you know, in

my COPD patients either, and I don't, I don't think that data like from the trials supportive to

be looking at that, I think we've got some data that really suggest, hey, we should be doing, we should be studying

this more, right? And I think we got a lot of data on bloodis and apples, but I think there's also, you know, like

looking at what those are to the airway and what, especially when we're talking about new coastal immunology for a lot

of these patients, like what's happening at the level of the airway, like looking at, you know, hopefully

over time, we'll be able to develop other biomarkers that, including, you know, there's phenode that

we're measuring from the airways, but there's certainly we see student eocinopholes and then be a little bit more predictive

than blood of having type two information in the airways. So I'm hopeful that we'll actually start seeing

better biomarkers over time with what's happening happening. You know, but you know, is a good reflector

of all of the connectivity. So I think it may be as the as the market

gets crowded with more biologic hopefully in COPD. Maybe a helpful tool that will if somebody's

failing one biologic high phenomena suggests, sorry, it's like we're doing asthma right now.

You know, so to the other team is the one that is linked to phenoproduction. I'll five definitely linked all

of them are linked to using it as biified particularly. So I think they may be helpful in

and also it's a pharmacodynamic biomarker actually. Now that doesn't usually correlate with clinical experience.

But if I see if you know come down from 40 to like 10, I feel comfortable that I'm targeting the area

of inflammation that I want to with the certain treatment. And you see that with certain biological and still

also. I think I'm very much with Stephanie. I believe what I'm going

to take from the data. It's enough data that it's worth studying and you would want to understand this.

One drawback theoretically that I see is that we haven't talked about alarmants a lot yet.

Maybe we will cover the little bit of this. That it seems not so easy to actually find

really the biology of alarms that are epithelia derived as is thinner to actually

a role in the modification of that disease process. And I would have hoped that anti-alarmant

therapies would teach us a little bit more about biology of the epithelia itself, including thinner

to actually understand whether it was this going. I think in all respect,

I think the duppy data have been so far more convincing in two clinical

trials. And the anti-alarmant data that we've seen so far, there's this clearly efficacy.

But it's not that clear cut to say, "Listen, hey, oh, that is, we know that which patients there are, we know how

where the benefit and the second one has not been as crisp and clear as we've seen with an hour

for our 13th antibody." And that is stimulus enough to, to

go on to understand that, but I think there's something that we don't know yet. And that's what Stephanie is saying. And I would have very much

agree. - I also just one quick get just what put up again for

what class was also saying about clinical biomarkers. Because I do think that's important here on what we should use and

what we should use. Like, I think, you know, chronic bronchitis was a,

was a eligibility criteria, right? Including criteria for the, for yes to notice trials. And actually,

it wasn't for Matt Nays, well, the most recent of that believes in Matt Nays, but they did see that actually,

the patients who had investigator and identified chronic bronchitis actually didn't have

the, Dr. Pads, some of the most, most benefit from the draw. So, so, it does look

like, hey, actually finding a symptomatic group, maybe, maybe particularly helpful. And, and

that's who we know that it works in. That said, you know, that drug did work over everybody, including

the people without chronic bronchitis, but if we're trying to figure out who might be have the most benefit. But something else that

we noticed is that, hey, as long as you had met eligible, even if you have empathyoma, which usually we wouldn't

think of as somebody who would benefit from one of these drugs. Well, if you also have exacerbations in chronic bronchitis,

even if you do have empathyoma, that some of those patients don't, you've seen to actually be to show

benefit. Now, they may not, we may have level setting there, you know, it's not like they're going

to get back to completely, you know, they're not going to feel 100% like maybe any household patient. That goes, uh,

it has a really amazing benefit from, from a biologic, but they, but they can have benefits. So I think that those

are also important parts that some of those clinical biomarkers that maybe, you know, some of them sort

of makes sense that some of them, hey, we actually had to kind of think about like, hey, maybe I can use this and fizzing the patient if you

still have kind of all the other, you know, you need all these other, uh, bound for

us. So I think that's important. I think it's important because before Syria comes in, I

just have to get back to this because I think I'm entitled as a, I may say this because I'm a co-author

of this data. I think there's a caveat still. The statement that people have been facemma and I'm saying

this as an author and I see this before responsibility and I know that we share the same view is not that

was not the perfect way to define or to rule out what level of diffusion capacity impairment.

So I I would believe that for all our listeners and for the discussion at say an emphasis,

as long as still the goal for me, my brothers, to reach because

it seems that this is something where we really need more data. They may have other types

of inflammation in them once the the tissue has vanished, once the vasculature and the airways of the smaller

ones probably are gone. So I'm a little uncertain about the statement that empathy might still qualify

for it, but I think we all agree. That's one of the holy gradals, if I may say, where we need interventions

on a on a pharmacological way, we would like to see a efficacy on if you allow me to. Yes,

no and I'm certainly not saying that it's the empathy targeted, but I am saying that,

hey, even if you have an empathy emancipation, I'm so teching, bloody ascent of those. I'm still thinking

about exacerbation on a pharmacological other symptoms that may not be unrelated or you know,

a different set of, you know, Thai, if you will or endotype, then what is happening with that empathy

in that, I still should be kind of thinking about whether or not you might benefit. And some of the nice things about these

drugs is like you don't have to. If it isn't working for you and you know, you found that out over time and you're not having

reductions in conservation and so on. And you can stop the drug. You're not going to have,

you know, but that's, you know, I'm a bit different take in a way from MPZ migraine with you, the clinical presentation

of these patients was mainly on self-reported. But let's not forget that MPZ MPZ mission have significant

small areas. This has been shown many, many years ago, we all are familiar with general papers

and now we have all these CT scans showing that they may have MPZ, but they still have

some small area plugging and mucus plugging. And I think the reason it may work in that population is not

just reversing a disease, which we don't have an evidence for, but it may affect the small area

function. And that's why what's interesting is, as common knowledge is, we don't measure area

function most of these patients, we measure large area function like medium size FV1. But we forget

to measure the small area function. And I know that there's lots of push now, including ATS,

we actually look at doing IO, you know, impedance oscillometry, looking at

more area function and not just concentrating on the FV1, which we know that right now

it's the holy grail for diagnosis of COPD. For now, but things may change. But I think

small area function is, but probably these biological, because they are given systematically, they don't have to be in hails,

so they do reach the areas where we want them. But there's some data on the side to constant, I was asked

about side to constant. At least I have 13, mostly in vitro data, that it can contribute

to destruction in the terminal long. And so hypothetically blocking

it may improve, but we don't have good TT evidence that we can reverse and presume about this at this

point. Is it also Dr. Hanani, I was maybe remodeling

of the small airways like a hastening at or helping with that not sure if there

any data or any radiological or mucus plug-in data or anything that we know so far. There

is a study ongoing looking at the pilum app and on small airway function and also on mucus plug-in.

Just like we did in asthma. The asthma study was published. There was a speech study. It's

clearly looked at small airway function, but also looked at mucus plug-in. You know the good news is we have protocols

now. We can actually count mucus plugs and actually Dr. Beth has been very on the forefront

of the type of imaging studies. I agree with Clouse imaging biomarker in these

in deciphering this is very very important. And I think so we can't mucus plugs radiologists now.

There are protocols. We're not doing it in real life yet, but I think we can measure airway wall thickness.

We can measure the, you know, any mass trapping and density of the

lung to measure exactly. So we don't need to do biopsies on these patients to know that there is an

effect. So I think they are, you're going to see, that's one of the big, unmeted, with biologing COPD. We need long

term data. We need mechanistic, warm mechanistic studies to understand why they feel better.

And can we actually reverse the disease? That would be a miracle if we can. And if we can, then

maybe we can just by using these air early in the disease process. Right now, we wait until the

horses out of the barn and then try to get maybe too late. They have burnt out lungs. Maybe if

we can show that there may be some delay in the disease progression. Then we can justify using

these biologics early in the NCOPD for example. Yeah, I think this is a really exciting idea of research right now.

So there's plenty of evidence from asthma that both the Pileumab and the Pileumab decrease mucus flux. And the Pileumab

is also been shown to decrease airway wall thickening. There's also improvement in ventilation defects in MRI. The only

study we have so far in COPD is a phase 2 study with the retroserocumab study with frontier 4 where they

found a reduction in mucus flux. And it was an numerical reduction but we have to keep in mind that these subjects weren't enriched

for people with high level of mucus flux. So you could assume that if you had a high level of mucus flux, maybe

they would be more effective. That's possible. But I think there's a lot of studies upcoming looking at these kind of imaging biomarkers.

And then the promise is you know you can target a small number of subjects and try to get a meaningful

effect. And potentially signals for disease modification, which is I think where we need to go, not just focus on

exacerbations. So to wrap it up, I think we're all very excited right with

all of the new knowledge that we have, but it's still quite a bit of unmet needs as Nick mentioned.

I want to just hear from each one of you what are, you know, the the future research needs with

patient selection with biomarkers, Oregon markers, and a lot of question also that could be extrapolated

from asthma and targeted therapies to COPD patients, like Stephanie mentioned, if it's not working

as a targeted therapy we can stop it. How do we know when to stop, when to switch, you know,

can patients maybe eventually de-escalate their controller inhaler medication,

things like that in general. I think one of the research needs,

not only biomarking drug and I think what is happening, that's what

my, it's a emotional side of this is where I believe we are witnessing something extremely

important. You mentioned it is early disease. The question is, if we

are prepared to actually interfere with an inflammatory response, resulting

in different end products, baschlor, alveolar, air, air, if you interfere early,

then that may treat a very different biology, you have may a much better opportunity to interfere,

but most important to me, as a clinician, it means that our whole classification of

diseases, with these interventions will come on the press, because we call and disease as

small as super-d, like a stalt recognition. Old, have smoked, looks like empathy,

my super-d, younger, sensitized, history, maybe more, as what will come on

the press is, if we really understand, like the oncologists, that doesn't matter whether it's quamazedino

or a creepy form, whatever. It's P53, ultra-translocation, each year of our positive-negative, as

a biomarker, there must be a immunological endotone, that would say listen, whenever

you age, the inflammation that you have and the symptoms that you present are impreensible.

A target for an intervention, X, Y, and Z. It doesn't matter what I call it. It's a mechanism that it would address,

and that is something that is really changing. I believe how we will address in the next years

and decades, obstructive lung disease, because we don't know whether where the limits of these are

and this debate of this is asthma, I don't know it, no you don't. The question is, what is the mechanism, what is the immunology,

what is the biology, and what is the target that you can identify? This is to me the most exciting

part of a completely new thinking around this disease.

So Sarah, to answer your question, I mean, I mentioned disease progression, that's a very important aspect, because right

now we are talking about the time called disease stability. There was a nice review recently, sorry as one

of the authors, I don't know if class was or definitely. In blue general on disease

stability, we don't use the remission yet in COPD, we do in asthma, but disease stability

may include more than one thing, exacerbation, flattening, symptom improvement, lung function decline.

That would be a very important thing to look. We need long-term studies, larger and maybe even on

less sick patients who are not going to out already. I think the effect of these biologic

safety wise on long-term is very important. We're dealing with a comorbid population or multimorbid.

I would say population effect on cardiovascular system because that's something that

hasn't been looked at systematically with these biologics. Are we targeting inflammation in the lung? Can we affect cardiovascular

comorbid? Because we know that there is a huge link between exacerbation and heart attack for example. I think

these are important issues and of course, mechanisms that is like CT scan like we mentioned looking at

what happens to mucus-plugging small area function are very important to enrich our knowledge,

but to make to reassure us that these drugs are different than other symptomatic inhalers that

we have. Not to undermine those, but so far, we haven't really done too much to move the needle

for COPD. We give them symptom relief, exercising, improvement, but we can't modify the disease program.

I agree with Nick, I think the thing that excites me the most is the potential, not proven yet of these biologics to potentially

modify disease. I think we know that most COPD tends to progress, not all, but most tend to progress, some faster

than others. And I think with these new imaging advances, I think we have potential surrogates to study disease

progression faster, and identify people who might be targets for altering that progression.

And then when it comes to progression, obviously, you have to look at short-term progression, long-term progression, same thing with stability, short-term stability,

and long-term stability. How long to give these biologics for is something you asked earlier? I don't think we know the answer

to that right now. There's not long-term studies. There's no reason to suspect why we shouldn't be giving this longer term.

The safety profile is quite good, but we know from asthma data that there can be almost like breakthrough, lack of treatment

effect. So I think we do need to keep close-fog on patients to see if we need to switch therapy. At this point, I think

we don't have data for stopping ICS, for example, or be drawing ICS. We do have to remember unlike in asthma, most

COPD have some element of nutrient-frequency information going on. So I would be very hesitant to stop ICS if they're doing

well, on triple therapy and on biologic. Without seeing the data that it's safe to do so, for now, I think I would probably just

continue. I will quadruple down on the disease modification

piece. I think we're still, we still don't really know how let's say if we wanted to look at early disease. So before somebody

got to kind of whatever their end stage is, you know, somebody at 70-year-old who's

got mild disease, are they going to continue? Are they going to continue to progress? Or are they just going to say like that versus

like a 40 or 50-year-old who, you know, maybe at that day, where

they're going to actually get, you know, be more likely to progress over time, but we don't know who those patients are

to put into a clinical trial. Who would I put into a trial? Because I'm like going to

have a trial that's like 10,000 patients? No, that's a reasonable. So I think we're still kind of working out some of those questions.

Like, you know, we've got resumes. There's a ratio,

a very function, you know, that route. But we don't really have kind of an understanding

of what are our biomarkers for what are our markers, for who's a browser that you might put

into these files. So I think that's an important piece. And I do think, you know, as the additional data

comes out on, let's say, the alarm and therapy, or we do think there might actually be, it might be

a little contact dependent, where some of those alarms, even though we know they work with take-o inflammation,

they may work, you know, in a doctor who's got different types of inflammation, they may work in a different way,

we're really impacting type 1 or type 3 inflammation. And, and are we going to learn more from those

drugs about squidweed, potentially, inter, you know, interfere on those pathways, or other

drugs that are now going to be independent, because we've seen some, you know,

we've seen some success, and now we're kind of thinking in this inflammatory immune paradigm

of, hey, let's hide to this precision medicine, I mean paradigm, like, can

we try to target this other group of patients, the majority of patients who don't have, or where

type two inflammation and targeting their type two inflammation isn't going to make, isn't going to meet, move the needle.

So I think that that's a very exciting place that I think we're definitely at, and I think we've got a lot

of people excited about it, the company is excited about, hopefully a lot of research like that.

But yeah, I think so, that would be mine. I think it identifying a high-risk population,

like Stephanie mentioned, we don't have a clue. We're trying to do that in asthma, by the way. But how do you define

high-risk population of rapid decline or rapid progression of the disease? We don't have good biomarkers

to identify these. Once we do, then we can do clinical trials on these patients early. You know,

we talk about pre-COPD, but there is at least three buckets that constitute pre-COPD, which one should

we study? Is it the one that has CT changes? Is it the one that I have symptoms? Is it the

one that has physiologic changes like DLCO, being lower, gastraphing, and we

have no idea. I think we need to put our heads together and come up with some kind of offer of the definition.

And what if we wanted to? That's that and how is the immune response, you know, or something? A lot of logic. Yeah,

by the way. I guess, sorry, you can you realize that we could talk about this for a while, but I'm sorry, that

one, and we're still upgithired. But I think what you're trying to put, what if I'd nice at this point in this

question is that we have a closing you. And this is, again, to the biomarker part.

So we ought to say, early intervention probably makes a lot of sense. If you modify something, don't do it in something that

has left the bar, because it's more plasticity, and you have an unknown sort of outcome.

And then the biomarker question comes, it gets completely new issue. This

is not a disease, severity, drug response biomarker. Now you're looking for risk

bias. And the risk biomarker is for it be something extremely different. You don't know any given

individual, so if you know within everyone of X at the age of 35 that is smoked, 10-peck years, what the outcome would

be. So genetic, early life events, infections, immunology.

So the whole area about risk stratification led by biomarker's clinical imaging,

genetic, immunological, cellular, that is a whole new area that people not need to

get into. Have it all the researchers that are on that, on that, on that, all young people. If you look

for an area, that is uncharted, it is one of those big things, wherever you are,

to look at risk stratification, Islamic disease, including the multimorbidities of that pattern.

That is uncharted territory, which is extremely good fun to go to.

That's awesome. That was really a great conversation. I want to thank you all, Dr. Bhatt, Dr.

Hanania, Dr. Christensen, Dr. Rabe, we're closing with you because you're on an international time zone and you're still able

to join us. So, thank you so much. We will close up in the next minute, any closing remarks

before that. Thank you, Sarah. Congratulations. Benio Pleasure. Hi, congrats.

Yes. It has been my pleasure and I congratulate, explicitly, ADS for doing this. So, having this from the assemblies

from young individuals, Sarah, if I may be too free to say that, to convene people like us, that sort of, you know, come from

different areas, congratulations for doing this. It's very educational and really hope that our listeners took something

from it to got inspired and got entertained to success. Thank you, thank you so much. Thank you so much. I very much

appreciate your time. We're going to also thank our listeners and we're missing

them and the front HES. Thank you.

Thank you for joining us today to learn more. Visit our website at thoracic.org. Find more podcasts

from the ATS assemblies on YouTube. Don't forget to like, comment and subscribe so

you never miss a show.